TNFα induces matrix metalloproteinase-9 expression in monocytic cells through ACSL1/JNK/ERK/NF-kB signaling pathways

• Published in: Scientific reports Vol. 13; no. 1; pp. 14351 - 11
• Main Authors: Al-Roub, Areej, Akhter, Nadeem, Al-Rashed, Fatema, Wilson, Ajit, Alzaid, Fawaz, Al-Mulla, Fahd, Sindhu, Sardar, Ahmad, Rasheed
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250; 631/337; Adipose tissue; Biosynthesis; c-Jun protein; Extracellular signal-regulated kinase; Gelatinase B; Gene expression; Humanities and Social Sciences; Inflammation; MAP kinase; Matrix metalloproteinase; Metalloproteinase; Molecular modelling; Monocytes; multidisciplinary; NF-κB protein; Phosphorylation; Plasma levels; Science; Science (multidisciplinary); Secretion; Signal transduction; siRNA; Transcription factors; Tumor necrosis factor-α; Western blotting
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-023-41514-6

Studies have established the association between increased plasma levels of matrix metalloproteinase (MMP)-9 and adipose tissue inflammation. Tumor necrosis factor α (TNFα) was elevated in obesity and is involved in the induction of MMP-9 in monocytic cells. However, the underlying molecular mechanism was incompletely understood. As per our recent report, TNFα mediates inflammatory responses through long-chain acyl-CoA synthetase 1 (ACSL1). Therefore, we further investigated the role of ACSL1 in TNFα-mediated MMP-9 secretion in monocytic cells. THP-1 cells and primary monocytes were used to study MMP-9 expression. mRNA and protein levels of MMP-9 were determined by qRT-PCR and ELISA, respectively. Signaling pathways were studied using Western blotting, inhibitors, and NF-kB/AP1 reporter cells. We found that THP-1 cells and primary human monocytes displayed increased MMP-9 mRNA expression and protein secretion after incubation with TNFα. ACSL1 inhibition using triacsin C significantly reduced the expression of MMP-9 in the THP-1 cells. However, the inhibition of β-oxidation and ceramide biosynthesis did not affect the TNFα-induced MMP-9 production. Using small interfering RNA-mediated ACSL1 knockdown, we further confirmed that TNFα-induced MMP-9 expression/secretion was significantly reduced in ACSL1-deficient cells. TNFα-mediated MMP-9 expression was also significantly reduced by the inhibition of ERK1/ERK2, JNK, and NF-kB. We further observed that TNFα induced phosphorylation of SAPK/JNK (p54/46), ERK1/2 (p44/42 MAPK), and NF-kB p65. ACSL1 inhibition reduced the TNFα-mediated phosphorylation of SAPK/JNK, c-Jun, ERK1/2, and NF-kB. In addition, increased NF-κB/AP-1 activity was inhibited in triacsin C treated cells. Altogether, our findings suggest that ACSL1/JNK/ERK/NF-kB axis plays an important role in the regulation of MMP-9 induced by TNFα in monocytic THP-1 cells.